Streptococcus pyogenes (group A streptococcus) is one of the most common pathogens infecting man, causing a wide range of infections from asymptomatic carriage to explosive, life-threatening infections. In spite of intense investigation by a number of laboratories, the periodic increase in severe streptococcal infections and the factors associated with these infections remain poorly understood. The advances made in understanding the basic biology and molecular genetics of this organism in recent years have provided the opportunity to examine heretofore unknown factors that may be involved in the virulence of the streptococcus. Gene loss and reacquisition via bacteriophages have been recognized to be key aspects in the evolution and transfer of extracellular bacterial virulence determinants. Additionally, novel mechanisms by which an organism alters arrangement of its genetic context to enhance expression of virulence determinants are also becoming better known. In this study, we propose to: 1) examine in detail the contribution of several recently identified potential extracellular virulence factors, including three new superantigens, a phage-associated protein, and CAMP factor, to diseases such as severe invasive infections and ARF and AGN, and; 2) further define the role of streptococcal bacteriophages in the evolution and transfer of extracellular virulence determinants. The results from these studies should not only identify new factors involved in virulence and pathogenicity of this organism, but also provide new insights into the molecular mechanisms governing the expression and regulation of these extracellular virulence determinants. This information will be essential for understanding the mechanisms by which group A streptococci are involved in disease and should facilitate new approaches for treatment and intervention aimed at reducing the morbidity and mortality associated with streptococcal infections.